Division of General and Bariatric Surgery,
Second University of Naples,
Via Pansini 5,
Naples 80131, Italy
carlo.tolone@libero.it

BACKGROUND: To evaluate whether the addition of a probiotic could improve Helicobacter pylori (H.P.) eradication rates and reduce the side effects of treatment in children.

METHODS: Between July 2008 and July 2011 all patients with a clinical, laboratory and endoscopic diagnosis of H.P. positive gastritis referred to our Unit were included in the study. Patients suffering from allergy to any of drugs used in the study, with previous attempts to eradicate H.P. and those who received antibiotics, PPIs or probiotics within 4 weeks were excluded from the present study. Patients were randomized into two therapy regimens (group A and B): both groups received standard triple treatment (omeprazole, amoxicillin and clarithromycin) while only group B patients were also given a probiotic (Probinul - Cadigroup). Patients compliance was evaluated at the end of the treatment. Successful eradication was defined as a negative 13 C-urea breath test (C13-ubt) result four weeks after therapy discontinuation.

RESULTS: A total of 68 histopathologically proven H.P.-infection children (32 male and 36 females) were included in the study. All of the patients in both groups used more than 90% of the therapies and no patients were lost at follow up. All side effects were selflimiting and disappeared once the therapy was terminated. Epigastric pain was observed in 6 (17.6%) group A vs 2 (5.8%) group B patients (P<0.05), nausea in 3 (8.8%) group A vs 1 (2.9%) group B patients (P<0.05); vomiting and diarrhea were observed in 2(5.8%) and 8 (23.5%) group A patients, respectively and never in group B (P<0.05). There was no significant difference between the two groups in terms of constipation (5.8% in group A and B). Four weeks after the completion of therapy, 56/68 patients (82.3%) tested negative for H.P. on C13-ubt. H.P. was eradicated in 26 patients (76.4%) in group A and in 30 patients (88.2%) in group B. There was no significantly difference in the rate of H.P. eradication between group A and group B (p=0.1), although the success rate for H.P. eradication was higher in group B than in group A.

CONCLUSION: The addition of a probiotic formula to triple therapy significantly decreased the frequency of epigastric pain, nausea, vomiting and diarrhea.

In both developed and developing countries, H.P. infection is most frequently acquired
during childhood, and it is associated with family size, familial clustering, low
socioeconomic status and education. The first line treatment for H.P. infection, as
recommended by the Maastricht 2–2000 Consensus Report , is a 7–14 days triple therapy
which includes amoxicilline, clarithromycin, OR metronidazole and a proton-pump inhibitor
(PPI) [2], though new strategies may be required for treatment both in adults and children. As
for adults, “infanti” treatment will fail in approximately 10-35% of patients, and H.P.
infection will remain resulting from several factors, including nonadherence to therapy
related to adverse effects or complicated dosing regimens and increasing antibiotic resistance
[3-5]. To overcome this problem, both in adults than in children, alternative and adjuvant therapies have been added to conventional treatment, such as probiotics (PB) [6,7]. Although
there is some controversy as to whether supplementation with probiotic improves the H.P.
eradication rates [8-10], several meta-analysis and reviews have suggested that probiotics can
improve the H.P. eradication rate by approximately 5-10% [10-13]. However, it is evident
that not all probiotics are created equal, that the beneficial effects are strain specific, and each
strain must be evaluated individually. Besides treatment studies on children are limited by the
small number of infected children in each individual center [14-16], therefore this study
aimed to evaluate whether the addition of a commercially multi-strain probiotics to a 7 days
triple therapy in children could improve H.P. eradication rates and reduce the side effects of
treatment.

Discussion:

It is well known that childhood is an important period for acquisition of H.P. infection.
Intrafamiliar trasmission of the infection , especially from mother to child, has been hypothisized as the major mode of dissemination [17]. H.P. is considered to be the major
cause of chronic gastritis and duodenal ulcer in childhood and an important cofactor in the
development of gastric cancer [18]. Unfortunately eradication therapy is not always
successful and reports of failed H.P. eradication therapy are increasing. Therefore, recent
review studies report eradication rates of standard triple therapy in children below 75%
[14,19]. Moreover this regimens have the disadvantage of risking poor compliance and
causing side-effects especially in children. Nowadays there is considerable interest in
alternative therapies or adjunctive treatment against H.P. to reduce some of the drawbacks
associated with the antibiotic consumption and to increase the eradication rates. Some
adjuvant therapy trials both in adults and in children incorporate probiotics [20-22].
In our study H.P. eradication was achieved in 82.3% of patients. A little increase in the
eradication rate and a significant reduction in side effects were observed in the group treated
with triple therapy plus Probinul PB. Resistant patients were offered to second line therapy
(omeprazole 1 mg/kg/d, amoxicillin 50 mg/kg/d and metronidazole 20 mg/kg/d), according to
NASPGHAN guidelines, confirming the contribution of a high background resistance to
clarithromycin. Also, guidelines on HP infection in children issued so far suggest that the
antibiotic susceptibility test should be performed whenever available [15]. However, we did
not performed susceptibility test for first line antibiotic therapy.

Probiotics include viable microorganism that have a beneficial effects for the prevention and
treatment of specific pathological conditions [23]. Principle mechanisms include interference with pathogenic toxins, preservation of cellular physiology , interference with pathogen
attachment and interaction with normal microbiota [24,25].

In addition, stimulation or modulation of immune responses, both within the lumen and
systemically, although not clearly linked to H.P. infection, may contribute [26,27]. Besides
probiotics may be beneficial in reducing adverse effects and increasing tolerability of HP
eradication regimens. Several studies evaluated whether probiotic supplementation might
help to prevent or reduce drug-related side effects during H.P. eradication therapy in adults
[28-30]. Up to date, in the pediatric population, few randomized studies have evaluated
whether consumption of probiotics could increase H.P. eradication rates and reduce the side
effects of treatment [31-33]. In fact, in a recent trial by Szajewska et al. [33] was identified
that the use of Lactobacillus GG along with standard triple therapy didn’t resulted in an
increased eradication rate and decreased overall therapy-related side effects.

Some of these trials do not provide evidence on the beneficial effect in children of
supplementation of probiotics to triple therapy for eradicating H.P. infection nor for
positively affecting therapy related symptoms and overall treatment tolerance [34].
However other investigators have shown that in symptomatic H.P. positive children, the
occurrence of antibiotic associated side-effects was significantly reduced by the addition of
probiotics compared with the placebo supplemented group [31].

H.P. eradication depends on a number of factor, including patients compliance, adverse
effects, bacterial resistance, poor drug distribution and concentration, socio-economic
conditions and geographic differences. So antibiotic related side effects may be depending on
different probiotic strains taken during the H.P. eradication therapy.In our study the choice of the Probinul probiotic formula was determinated by the fact that it contains high concentration of a wide range of bacteria, as well as inuline as prebiotic.
Previously we have demonstrated that this probiotic formula was able to reduce antibiotic
gastro-intestinal related side effects in children treated with amoxicillin therapy for
pneumonia infections [35].

Besides De Bortoli et al. have demonstrated that the addition of bovine lactoferrin and this
probiotic formula to standard triple eradication therapy could improve the H.P. eradication
rate and reduce side effects in adult [36].
In this study the combination of standard triple therapy + probiotic + bovine lactoferrin was
more effective than triple therapy alone. This could be explained by the combined effect of
the bactericidal and bacteriostatic properties of bovine lactoferrin and the mechanism of the
probiotics including their direct, nonspecific, bacteriostatic activity and their enhancement of
immunoglobulin A production [37].

Probiotics may act through both immunological as well as non-immunological mechanism in
H.P. eradication. The latest mechanism includes providing antimicrobial substances,
competing with H.P. for adhesion and providing a mucosal barrier. When there are decreases
in side effects, compliance improves [26]. The efficacy of probiotic supplementation for
reducing side effects during the course of anti HP regimens appears to be dependent of which
probiotic species are used. In fact probiotics must be metabolically active in the intestinal
lumen, where they should survive but not persist after the therapy regimen has been
completed. They must be acid and bile resistant and should be antagonist to pathogenic
bacteria [38-40].

The present study has shown that the addiction of the Probinul probiotic formula to standard
antibiotic treatment reduced in children H.P. therapy-associated side effects (occurrence of
side effects: 61.5% in group A vs 14.5% in group B). The H.P. eradication was achieved in
26 of 34 patients in group A (76.4 %) and in 30 of 34 patients (88.2%) in group B. Although
the success rate was higher in group A than in group B, the different was not significant.
Also, we preferred to use the conventional 7-days triple therapy to better highlight the
efficacy of probiotic supplement; furthermore extending the duration of therapy form 7 to 14
days is not clearly associated with an increased eradication rate [41]. However, our study
presents some limitations, as a relative small number of patients and absence of a placebocontrol
group for the probiotics; also, the treatment group with probiotics is likely to be
superior to the control group if the sample size is larger.

In conclusion our study suggests that the addition of this probiotic formula to triple therapy
did not increase (significantly) the H.P. eradication rates; however it significantly decreased
the frequency of epigastric pain, nausea, vomiting and diarrhea.
In children with H.P. infection, we think, there is evidence to recommend the use of this
probiotic formula along with standard triple therapy as an option for decreasing overall
therapy related side effects and slightly increasing the eradication rates.